1. Field of the Invention
The present invention relates to a composition for treating multimorbidity with one drug, comprising a drug combination of kampo medicines, wherein the composition improves a cognitive function in Alzheimer-type dementia or mild cognitive impairment and treats at least one disease from the group consisting of overactive bladder, constipation, and chronic kidney disease complicated by them with one drug.
2. Description of the Related Art
As in the publication by Boyd et al. in JAMA in 2005 (Boyd C. M. et al., JAMA, 294(6): 716-724, 2005), multimorbidity is defined as the coexistence of 2 or more chronic diseases simultaneously. It has been reported that 67% of 30,923,846 people who were continuously enrolled in Medicare during 2008 in U.S.A. were affected by multimorbidity and the prevalence of multiple chronic diseases increases with age to 81.5% at 85 or more years old (Marcel E. Salive et al.,: Multimorbidity in Older Adults. Epidemiology Reviews, Vol 35, Issue 1, 1 Jan. 2013, 75-83, https://doi.org/10.1093/epirev/mxs009). It has been reported that in an examination of the frequency of multimorbidity focused on only 40 chronic diseases in the U.K., 42.2% were affected by only one disease and 23.2% were affected by multimorbidity having 2 or more diseases (Anthiens S et al., BMC Fam Pract, 11:65, 2010). As a result, the existence of multiple chronic diseases naturally increases the number of administered medicines. The study of 700 elderly persons by Fushiki et al. at Jichi Medical University reported that men and women at an average age of 79.5 take an average of 6.36 drugs, and polypharmacy with 5 or more drugs was 63% (Fushiki Y et al., General Medicine, 15(2): 110-116, 2014). In addition, a cohort study by Green et al. reported that one more prescriber for a multimorbidity patient increases drug adverse events by 29% (Green J L et al., Am J Geriatr. Pharmacother, 5(1): 31-39, 2007). In other words, multimorbidity is the biggest cause of polypharmacy and polypharmacy is the biggest cause of the increase of side effects due to drugs and the increase in drug cost and medical expense, and has therefore been a global problem. Currently, guidelines for single chronic diseases exist for each of a large number of chronic diseases, but since the guidelines for single chronic diseases are not indicated for multimorbidity, the existing guidelines cannot now be used for multimorbidity. Only the guidelines having a description of recommendation for cases with multiple complications are those for diabetes and angina. It is the present conditions that no accurate guidelines for the multimorbidity exist. Studies on how to actually deal with multimorbidity is necessary (Smith S M et al., BMJ, 345: e5205, 2012) and the website of The Johns Hopkins School of Medicine emphasizes that studies for preventing multimorbidity should be promoted (Boyd C et al., Center for Health Care Strategies. Inc., 2010).
Also in Japan, it has been reported that, according to the statistics of the Japan Society of Ningen Dock (complete medical check), the super normals, who don't have abnormality in any of the basic items, were 29.8% in 1984, when the aggregation of the results started, but decreased every year to 6.6% in 2014, which was the lowest ever (Japan Society of Ningen Dock: Report on National Aggregate Results of Ningen Dock in 2014, 2014). It is considered that multimorbidity is certainly increasing and the development of the measures is urgent business.
Dementia is an intellectual disability caused by acquired causes and roughly classified into Alzheimer-type dementia, mixed dementia of Alzheimer-type dementia and cerebrovascular dementia, cerebrovascular dementia, dementia with Lewy bodies, normal pressure hydrocephalus, and frontotemporal syndromes. The main diseases of senile dementia-related diseases are Alzheimer-type dementia and cerebrovascular dementia, which account for 75% to 80% and Alzheimer-type dementia is considered to be predominantly at a higher rate. The prevalence of dementia at 30 years or older is reported to be 4 to 6% in developed regions in Europe, the Americas and the West Pacific, but increases to 20% to 33% for elderly persons at 85 years or older. Patients with dementia will continue increasing at a ratio of 4,600,000 people/year from now and are estimated to increase to 42,300,000 in 2020 and to 81,100,000 in 2040, and it is considered that dementia will increase rapidly all over the world from now on (Ferri C P et al., Lancet, 2005; 366: 2112-2117). In other words, while Alzheimer-type dementia has been increasing, it is the biggest problem in that no therapy for dementia, including Alzheimer-type dementia, except normal pressure hydrocephalus and cerebrovascular dementia, has been established in the present, because the cause has not been determined.
Mild cognitive impairment (MCI) is a concept proposed in 1999 by Petersen et al. (Petersen R C, et al., Arch Neurol, 56: 303-308, 1999) and diagnostic criteria (Petersen R C, et al., Arch Neurol, 62: 1160-1163, 2005) newly proposed by Petersen et al. in 2003 are used for the diagnosis of mild cognitive impairment (MCI) now. In other words, mild cognitive impairment is defined to be a condition in which there are claims of cognitive decline from the subject oneself or his family, cognitive functions are not normal, but without meeting the diagnostic criteria for dementia, and there is a minimum disorder in complicated daily life movements, but basic everyday life can be spent normally. In other words, no behavior and psychological symptoms of dementia (BPSD) is observed in mild cognitive impairment (MCI). It has been reported that as a result of a follow-up study by Petersen et al. at Mayo Clinic of subjects with MCI by their criteria for 15 years or more, the subjects progressed to dementia or probable AD at an average ratio of 12% per year and about 80% developed dementia in 6 years (Petersen R C, et al., Mild cognitive impairment, New York: Oxford UP; 2003, P. 15-39). From this result, it is considered that improving mild cognitive impairment (MCI) would naturally reduce the patients who develop Alzheimer-type dementia. However, the results of clinical trials with donepezil hydrochloride for MCI were reported in 2005, and it was reported that progress of dementia can significantly he suppressed by intake of donepezil hydrochloride for one year, but there is no preventive effect on the disease progression afterward (Petersen R C et al., N Engl J Med, 2005: 352: 2379-88), indicating that administration of donepezil hydrochloride eventually results in the same course of cognitive decline as that without treatment after one year. In other words, like there is no effective drug that improves cognitive functions in Alzheimer-type dementia developed, no effective drug that ameliorates cognitive decline has been successfully developed also for mild cognitive impairment (MCI) (Doody RS et al., Neurology, 72: 1555-1561, 2009).
Multimorbidity is easy to occur in Alzheimer-type dementia or mild cognitive impairment and complications with constipation and/or overactive bladder are developed at a high rate as an autonomic nervous system disorder. In other words, the frequency of normal chronic constipation is reported to be 0.7 to 79% (median 16%) according to systematic review (Mugie S M et al., Best Pract Res Clin Gastroenterol, 25(1): 3-18, 2011). Since most of patients with Alzheimer-type dementia or mild cognitive impairment are old in age, constipation is a frequently observed complication. It has been reported that among 7,758 elderly persons in nursing facilities or at home, 73.7% have cognitive impairment and 1,967 persons (25.4%) have constipation (Takaue Sachiko et al.: Fact-finding of excretion care for elderly person in Mie Prefecture. Mie nursing journal, 9:111-116, 2007).
As to overactive bladder, Irwin et al. have reported that 11.8% of general population at 18 years or older has overactive bladder and the frequency increases with age (Debra E. Irwin et at, European Urology, 50: 1306-1315, 2006) and it has been reported that incontinence is very common in elderly persons and it is observed in 5 to 10% of at-home elderly persons and about 50% of elderly persons in institution (Kikuo Okamura, et al., Guidelines on Urinary Incontinence in the Elderly (http://www.negg.go.jp/hospital/iryokankei/documents/guidelines.pdf), P. 6-15). Furthermore, it has been reported that 44% of patients with Alzheimer-type dementia have nocturia, which is one of the diagnostic criteria for overactive bladder (Takahashi O et al., J Am Geriatr Soc, 60: 2370-2371, 2012).
Furthermore, the number of patients with chronic kidney disease (CKD) in U.S.A. is about 13% of the adult population according to National Health and Nutrition Examination Survey (NHANES). In Japan, the number of patients with chronic kidney disease (CKD) is reported to be 13% of the adult population and 13 million persons (Imai, E., et al., Clin. Exp. Nephrol., 11(2), 156-163, 2007). Cardiovascular Health Cognition Study has indicated that moderate renal dysfunction increases development of dementia by 37% (Seliger S L, et at, J Am Soc Nephrol, 15: 1904-1911, 2004). Furthermore, most of Alzheimer-type dementia patients are easy to have decreased renal functions due to the age since they are old and easy to have complications with chronic kidney disease (CKD).
In other words, Alzheimer-type dementia and mild cognitive impairment are complicated by constipation and overactive bladder at high rates due to autonomic nervous system disorders, and complications with chronic kidney disease are found frequently and multimorbidity is observed frequently. However, no effective guidelines for any combination of Alzheimer-type dementia or mild cognitive impairment and complication diseases thereof and no therapeutic agents specific for this multimorbidity exist.
Only therapeutic drugs for Alzheimer-type dementia are 3 acetylcholinesterase inhibitors (donepezil hydrochloride, galanthamine, rivastigmine) and 1 low affinity N-methyl-D-asparagine receptor antagonist (memantine). These are medicines for ameliorating symptoms and the effect of any drug on cognitive function is transient. These cannot suppress progression of Alzheimer-type dementia and no radical therapeutic effect is expected. The clinical trial with an active amyloid vaccine produced based on the hypothesis that the cause of Alzheimer-type dementia is β amyloid, as a radical therapy, was canceled because of meningoencephalitis. In the subsequent course, it was indicated that the accumulation of amyloid β in the brain was reduced, but the progression of dementia could not be suppressed (Lannfelt L et al., J Intern Med, 275: 284-295, 2014).
The therapeutic agents for Alzheimer-type dementia currently used in general themselves have the side effects of constipation, pollakiuria, and urinary incontinence. Therapeutic agents for overactive bladder other than mirabegron have the side effect of constipation, and solifenacin and mirabegron have the side effect of increasing creatinine. As a result, treatment of Alzheimer-type dementia and mild cognitive impairment, which are complicated by constipation, overactive bladder, and/or chronic kidney disease at a high rate is very difficult and easy to result in polypharmacy.
Even now, to patients with Alzheimer-type dementia or mild cognitive impairment complicated by constipation, overactive bladder, and/or chronic kidney disease, drugs for respective diseases are administered without any hesitation, resulting in polypharmacy. Therefore, the side effects become complicated and the frequency of side effects will be increased. It is also a problem in that the interaction of drugs has been studied only for two drugs and the interactions and side effects in polypharmacy are difficult to expect.
As to kampo medicine therapies, Jingui Yaolue written in the early third century A.D. describes an instruction to administer boijioto for dementia. However, the results of studies have indicated that administration of kampo medicines for Alzheimer-type dementia ameliorates symptoms such as behavior and psychological symptoms of dementia (BPSD), but there is no kampo medicine having a radical therapeutic effect that improves cognitive functions in the long term. Yokukansan, which is used the most often for Alzheimer-type dementia, is administered for BPSD (Hideki Okamoto et al., Neuropsychiatric Disease and Treatment, 10, 1727-1742, 2014). The 2017 Therapeutic Guidelines for Dementia by the Japanese Society of Neurology states that yokukansan is used for the suppression of BPSD in dementia with Lewy bodies (the Japanese Society of Neurology: The 2017 Therapeutic Guidelines for Dementia., 254-256, 2017). Moreover, when the BPSD suppressing effect is not obtained only with yokukansan, additional administration of orengedokuto, which is used for cerebrovascular disorder-related dementia, resulted in the suppression of BPSD, but the improvement of cognitive functions has not been described (Hideki Okamoto et al., Neuropsychiatric Disease and Treatment, 9, 151-155, 2013). In other words, this not only fails to improve cognitive functions, but also is totally far away from and unrelated to a drug for the purpose of relieving constipation, overactive bladder, and chronic kidney disease, which are other diseases that are complicated by Alzheimer-type dementia or mild cognitive impairment at high rates, with one drug and it is something totally different. There is a report that the administration of Hangebyakujutsutemmato improved cognitive functions (Yoshiharu NAKAE, et al., Kampo Med, 64, 104-107, 2013), but the observation period was 4 weeks, and it cannot relieve constipation, overactive bladder, and chronic kidney disease, which are diseases that are complicated by Alzheimer-type dementia frequently, more than considered to be only temporary like donepezil hydrochloride. In other words, despite of studies for a very long period of 1700 years to develop cognitive function-improving medicines for Alzheimer-type dementia and mild cognitive impairment, the development of a kampo medicine that improves cognitive functions has been extremely difficult and no one in the art has been able to develop a drug that ameliorates multimorbidity of constipation, overactive bladder, and chronic kidney disease, which are complicated by Alzheimer-type dementia and mild cognitive impairment frequently, with one drug.
Moreover, although various kampo medicines including Bofutsushosan have been used for constipation (Norio Iizuka et al., Frontiers in Pharmacology. 6. Article 73.2015. www.frontiersin.org) to get results, kampo medicines mainly including Goshajinkigan have been used for overactive bladder (Tomonori Miyagawa et al., Int. J Urol., 22, 254-263, 2015), and kampo therapeutics such as Boiogito have been used for chronic kidney disease (CKD) (Hong Wei Zhang, et al., Cochrane Database of Systematic Reviews, 10, 1-21, 2014), there are few medicines for overactive bladder and chronic kidney disease that have been clinically recognized and yielded long term results.
In recent years, Alzheimer-type dementia and mild cognitive impairment as well as diseases complicated by them have markedly increased. However, in multimorbidity of Alzheimer-type dementia or mild cognitive impairment, it is very difficult to relieve these diseases themselves and each individual disease of constipation, overactive bladder, and chronic kidney disease complicated by them. Moreover, since this multimorbidity is a collection of diseases in different fields that are a digestive organ disease, an urinary organ disease, and a renal disease complicated by a neurological disease, there is not even an idea of relieving these multiple diseases with one drug at the same time, and therefore there is no researcher or person skilled in the art of kampo medicines who studies drugs that can treat diseases complicated in these multimorbidity at the same time with one drug. Naturally, there is no report of research findings on these therapeutic agents for multimorbidity and consequently, there is no such drug.